. The long-term goal of this project is to determine the mechanism(s) by which an environmental agent such as lead (Pb) interplays with genetics to influence the onset of an autoimmune disease such as Systemic Lupus Erythematosus (SLE). Susceptibility to SLE is known to be under complex polygenic control and is thought to be influenced by environmental agents capable of modulating the immune system of individuals with a genetic liability. The goal of this proposal is to pursue the hypothesis that environmental toxicants contribute to the triggering and exacerbation of SLE. The focus will be on the effects of Pb on susceptibility to SLE by taking advantage of a new model in New Zealand Mixed (NZM) strains of mice. These recombinant inbred strains were derived from the parental strains of the classic NZB x NZW Fl hybrid female SLE model; the mixtures of susceptibility genes, inherited from the ancestral genomes by recombination and segregation, contribute to phenotypic differences of nephritis, CNS lupus, and other autoimmune phenotypes. The NZM strains, therefore, offer a new way of looking at the effects of the environment on triggering or exacerbating SLE in a closely related set of lupus-prone, H-2 identical strains. The novel advantage is that some NZM strains with partial or low penetrance of autoimmunity may be more informative than mice at the extremes of susceptibility or resistance. The Specific Aims are: (1) determine the effects of Pb exposure on the time course, severity, morphogenesis, and immunopathology of autoimmune immune-complex-mediated nephritis and CNS pathology in selected NZM strains with high, partial, and low penetrance. (2) ascertain effects of Pb on manifestations of B-cell autoimmunity to include strain-specific patterns of anti-dsDNA and anti-chromatin autoantibody profiles, Coombs' positivity (anti-erythrocyte autoantibodies), anti-phospholipid, and B-cell hyperactivity. (3) assess T-cell activation and cytokine profiles (IL-2 and IFNg vs IL-4 and IL-5) and accessory cytokine levels (IL-1, IL-6 and TNFa) and 4 evaluate the involvement of hormonal patterns in disease modulation. The proposed research will provide basic information on the effects of Pb on SLE susceptibility in individuals with variable numbers of threshold liability genes, in identifying SLE genes, and a general understanding of the extent to which environmental factors may influence autoimmunity and autoimmune disease.